Jennifer Markarian is manufacturing reporter for Pharmaceutical Technology.

Jennifer Markarian

Although the pharmaceutical industry is criticized for its slowness to accept change, it has made manufacturing improvements in the past decades in response to changes in drug delivery (e.g., multi-layer tablets and prefilled syringes); market demands for cost-efficiency and the flexibility to make smaller batches; and regulatory demands for higher product quality, process robustness, and worker safety. Advances in automation, process control, and connected systems have been adopted. Continuous manufacturing has not replaced traditional batch manufacturing, but its concepts are better understood and accepted, and the first commercial, continuous solid-dosage processes are up and running (see pg. 48 in this issue for more on continuous manufacturing). 

	Parenteral manufacturing and fill/finish

	The pharmaceutical industry’s aging manufacturing facilities, particularly for parenteral drugs, have been pointed to as a cause of drug shortages, and organizations such as the Parenteral Drug Association have taskforces dedicated to overcoming the challenges to modernization, including post-approval changes (1). In many facilities, however, modern technologies have been implemented and shown to improve efficiency, quality, and flexibility. 

	One of the keys has been removing human intervention with automation and cleanroom systems, such as restricted access barrier systems (RABS) and isolators. “RABS achieves the sterility assurance level required by regulatory authorities and allows for rapid product changeover along with high safety,” explains Bernd Stauss, senior vice-president of Pharmaceutical Production/Engineering at Vetter Pharma-Fertigung. An improved RABS concept called Vetter CleanRoom Technology (V-CRT) combines the advantages of both isolator and RABS technology with fully-automated decontamination of the cleanroom using hydrogen peroxide, says Stauss. 

	Blow-fill-seal (BFS) technology is another aseptic technology that reduces human intervention. In the automated process, containers are formed, filled, and sealed continuously; BFS is particularly useful for single-dose containers and terminally sterilized drug products (2). 

	Other new drug-delivery systems, such as prefilled syringes and autoinjectors, and the development of ready-to-fill syringes, vials, and cartridges resulted in more flexible machine platforms for filling different formats. Automated inspection improves quality. In addition, 100% in-process checkweighing prevents product loss, adds Christian Treitel, director, Business Development Pharma, Bosch Packaging Technology.

	The use of robots, particularly in fill/finish, continues to expand (3). Robotics were being used at Vetter by the 1990s, notes Stauss. Fully automated lines with robotics are the way of the future, says Treitel, who adds, “Connected industry solutions will bring more intelligence into production. These technologies will help achieve higher productivity, safety, and efficiency.”

	Containment for highly potent drug manufacturing

	Improvements in containment for working with highly potent drug substances have been driven by the growing use of highly potent APIs in solid-dosage drugs and antibody drug conjugates, as well as a push for better protection of workers and prevention of cross-contamination. Concepts such as occupational exposure bands (OEBs) and occupational exposure limits (OELs) allowed better definition of drug hazards and the containment strategies needed to handle them safely. “OEBs/OELs were used in the United States first, and Europe started to use them around 15 years ago, followed more recently by Asia,” notes Richard Denk, head of the Containment Group at SKAN. European guidelines published in 2014 (4) that require setting permitted daily exposures (PDEs) for each product have led to better data availability as well as an increasing need for containment equipment. 

Equipment innovations, such as new technologies for isolators and product transfer systems, have made it easier for manufacturers to operate under low OEL conditions, but there is still room for improvement. Robotics, for one, are poised for implementation in this area and would remove human intervention. In the future, equipment such as fluid-bed dryer or a high-shear mixer would benefit from being designed for integrated containment rather than being adapted for containment after the fact, suggests Denk.  

	Capsule filling equipment has progressively obtained increased speeds, higher efficiency, and greater flexibility, along with quality measures such as automated weight control and inspection. “Dosing accuracy has become an essential feature of capsule filling machines,” says Treitel at Bosch Packaging Technology. 

	A significant change in capsule filling has been the type of products filled. “Over the past 10 years, the production of capsules containing multiple products has increased,” says Stan Matthews, sales manager of the Processing division at MG America, the US subsidiary of MG2 of Italy, which celebrated its 30th anniversary in its New Jersey headquarters in 2017. “Combinations could include, for example, two different types of pellets, tablet and pellet, or powder and pellet. Machines that are capable of filling powder, pellets, tablets, micro-tablets, and other forms on one capsule filler give manufacturers flexibility. On-board weight-control systems are capable of measuring and controlling the net fill weight of multiple components in each capsule. These changes are driven by continued changes in market demands from consumers and new advances in pharmaceutical development.  A new trend in capsule filling technology is the continued push toward continuous manufacturing.”

	In addition to these new dosage forms, Treitel points to increased yield, using the tamping pin principle as another significant introduction. “Today, powders are dosed on high-performance tamping pin stations with minimal product loss,” says Treitel. “Further requirements for capsule filling machines are combination filling, inline weighing systems that offer secure and documented processes, and containment applications in several versions for highly potent active substances. In the past 5–10 years, the focus has been more on small batches and flexible machines, as well as process analytical technology. The pharmaceutical industry is also requesting quicker product change over and shorter cleaning cycles.” 

	Tablets were a widely used dosage form 40 years ago and still are today, but the equipment used to make them has been transformed in efficiency, quality, and even safety of operation. Increasing automation and connected, “smart” machines are leading the way into the future, which is likely to see greater integration of tableting into continuous solid-dosage processes. 

 spoke with Matt Bundenthal, direct sales and communications manager at Fette; Alex Bunting, marketing manager at I Holland; Fred Murray, president of KORSCH; Michael Fazio, sales manager, Batch & Continuous Processing Systems at L.B. Bohle; and Dale Natoli, owner and president at Natoli, about how tableting has changed and what they expect for the future.

 What have been the most significant changes in tableting in the past 40 years and in the past five or 10 years? What have been the drivers for these changes? 

 The most significant changes in the world of pharmaceutical tableting is related to advancement in drug-delivery methodologies. The focus on simple, single-layer, immediate release therapies has been replaced by a wide range of innovative delivery platforms including bi-layer, tri-layer, and tablet-in-tablet technologies. Most recently, microchip in tablet technology has been developed to improve compliance with critical therapies. Extended-release products, combination products, and the ability to deliver drug substances exactly where and when they are needed have driven these changes.  The equipment manufacturers have responded with specialty machines that facilitate these new tablet formats, both for product development and on a commercial scale.

	A second significant change is related to the clear focus on operational efficiencies and flexible equipment. Many years ago, it was not unusual to tour a manufacturing facility and see only a small percentage of the equipment in operation. Today, under significant pricing and competitive pressures, there is a major emphasis on overall operating efficiency, uptime, and product yields. The development of new and innovative drug delivery platforms requires flexible equipment that can produce a wide range of product formats, with fast changeover, for maximum utility. Today, a single tablet compression machine can produce single-layer, bi-layer, tri-layer, and tablet-in-tablet products, in combination with an exchangeable turret capability, to facilitate the production of literally any tablet size and format, with high efficiency.

	In the past five years, continuous manufacturing has also been established as a viable alternative to batch processing. For some products, continuous manufacturing technology offers significant advantages for new product development and scale-up, increased product quality, and reduced operator intervention. 

 The reintroduction of the multi-tip tool has created significant changes in tablet manufacturing. Recent developments in multi-tip tooling include assembly-type punches, which reduce costs by allowing the reuse of punch bodies and repair or replacement of individual punch tips. Vented caps allow the cleaning of punches as an assembled unit and the use of compressed air to remove residual moisture. The development of multi-tip reject verification tools provides the assurance needed by the pharmaceutical industry to validate tablet sizes and weights, making multi-tip tooling a viable option. These technological advances in multi-tip tooling, made within the past 10–15 years, have greatly increased tablet production, which reduces operational costs by saving energy, minimizing labor, and decreasing manufacturing footprints. These benefits are driven by continued pressures from both regulatory bodies and the pharmaceutical industry.

 The requirement for higher productivity and efficiency, while maintaining top quality tablets, has become more prevalent during the past 40 years, and innovations have advanced to keep pace with the ever-growing demand driven by developing markets to produce tablets for the masses. Perhaps one of the major advancements has been multi-tip tooling, which has helped to cater to this demand. Multi-tip tooling has transformed the quantity of tablets produced and it is now considered the most productive form of tablet manufacture where it can be applied. A difference in the past decade is the request for reduced lead times; multi-tip tooling has helped to keep these lead times and allow manufacturers to meet the time-to-market demand.

	The influence of developing countries is also a huge driver for change. Due to increasingly strict controls and standards, these countries are aligning with good manufacturing practices (GMP) and regulatory demands, with production volumes increasing at an astounding rate. The developing world must comply to GMP and regulatory requirements to distribute their products globally, which requires major investment in upgrading manufacturing facilities. I Holland is working in these countries to help them develop their processes and products. 

 Changes in tablet press technology can be correlated with the need for a higher degree of control over finished tablet quality, at higher machine speeds; the requirement for presses that can efficaciously compress more challenging formulations; a request from end users for maximum versatility in machine design; and cost-cutting targets, relating to issues such as final yield percentages. 

	The introduction of pre-compression represents one of the most significant-and useful-changes. It greatly increases overall compression efficacy by helping eliminate entrapped air and reducing the incidence of phenomena such as capping and ‘picking.’ Real-time compression force monitoring and control, and the subsequent ability to automatically reject out-of-spec tablets, has led directly to increased machine speeds, better quality control, and improved yields. Computer-controlled, recipe-driven machines ultimately improved repeatability across batches, with reduced set-up time. The appearance of motorized feeders (and the elimination of ‘open’ or gravity feeders) improved die-filling characteristics. Enhancements to multi-layer functionality, especially for bi-layer tablets, include  dynamic first-layer sampling, prevention of cross-contamination, and weight control for individual layers. Inventions such as removable turret assemblies revolutionized fast changeover. The growth of potent compounds led to high-containment technologies, such as wash-in-place features, glove ports, door interlocks, and rapid transfer ports.  And the need for greater operator safety led to additions such as guards and shrouds surrounding turrets, switch-controlled interlocks on access doors, protected discharge chutes, and electro-magnetic brakes.

 Pharma manufacturing has come a long way in terms of mechanical engineering controls.  Over the past 15–20 years, we have experienced a trending demand for highly contained capital equipment; more often, our clients’ formulations include a potent API. Contained oral solid-dosage equipment projects can be sophisticated and challenging because process air handling and mechanical interfaces must be more tightly managed. Contained process equipment serves as protection of both personnel and pharmaceuticals products alike. 

	Automation, process control, and process analytical technology (PAT) has also changed, and has become crucial to ensure high-quality production of pharmaceutical products. 

 What trends or new developments do you foresee for the near future?

 Tablet press manufacturers continue to design machines that offer ever-increasing versatility. Another trend is integrating tablet presses into continuous manufacturing lines, using control systems with up- and downstream control ‘handshakes.’ In addition, features allow presses to ‘talk’ to and send data to a client’s in-house network. 

 Continuous processing is a developing manufacturing platform for the future. We have experienced an increasing number of end-user pharmaceutical companies evaluating their drug candidates on our fully continuous manufacturing line in our Pharmaceutical Technology Center, which was built in 2014. Pharmaceutical manufacturers and FDA see merit in and support the evolution of pharma manufacturing from batch to continuous because of inherent features, such as smaller footprint, faster and less costly scale up, flexible batch sizes, and improved quality. 

 As the industry works toward continuous manufacturing, tool-to-die clearances will become even more critical in the near future. These tolerances will necessitate tooling to be engineered to meet the needs of specific powder characteristics and particle sizes. Furthermore, current estimates indicate that only 15–20% of the pharmaceutical industry use multi-tip tooling, and we predict that this usage will increase due to its advantages. 

 The pressure for shorter lead times and cost efficiency is leading companies to investment in new technologies and processes. On top of this, stringent quality requirements drive the need to improve production from end to end, through durable tablet tooling and the associated maintenance equipment.

	The adoption of continuous manufacturing, I think, will be an important trend in the future and one which will help in reducing reaction time and time to market. The challenge, then, is for the upstream and downstream processes to keep up with each other. In the case of a quality tooling manufacturer, we continue to develop even more ways to maximize uptime by producing solutions to problems that compromise the maximum output and yield. I Holland is working toward this goal with the introduction of XDF (eXtended Dwell Flat), a novel, patented, elliptical head form which has been designed to increase dwell time on existing presses without the need for expensive modifications. As the importance of increased productivity continues to grow, XDF can give users higher press speeds for challenging products and formulations, enhancing tablet compaction and cohesion.

 These trends of more complex drug delivery platforms, and an increased emphasis on operating efficiencies will continue. The use of continuous process technology will also be more widely used and accepted. From an equipment perspective, tablet compression machines are going to become smarter and more connected. They will self-diagnose, include on-board help systems to guide the user through every aspect of the operation and maintenance, and be fully integrated to central SCADA [supervisory control and data acquisition] and manufacturing execution systems. They will monitor and report on operating efficiency, and leverage new technologies to permit remote support by service experts. 

	Harlan Hall, who founded The Coating Place 41 years ago, worked indirectly with Dale Wurster, the inventor of the Wurster fluid-bed coating process, and the protoype equipment he created. Hall shared his perspective with 

 How has the Wurster coating process for pharmaceutical tablets changed over the past decades? 

 Prior to the mid-1970s, use of the process was limited to a few companies, mostly coating fairly large particles. In the 1970s, the Wisconsin Alumni Research Foundation (WARF) did extensive work in extending the practical use of the Wurster process to smaller particles (as low as 10 micron) and helped develop a number of new products using this technology. This work continued when Coating Place was founded in 1976 and began providing contract services using this technology. In the mid to late 1970s, equipment manufacturers adopted many of the innovations pioneered by WARF, and coating of smaller particles became more common. Innovations including continuous clean filters and larger expansion chambers became industry standard, and improved Wurster plate design and linear scale-up pushed the state of the art.

	The development in the 1970s of taste-masked dosage forms, and particularly chewable and liquid-dosage forms, arose from the ability to manufacture small, coated particles at commercial scale.  As equipment to prepare experimental quantities of such particles became more common, more pharmaceutical companies became familiar with Wurster technology, leading to new products. The development of water-based coatings allowed more companies to pursue this work without need to be concerned with control of solvent emissions.

A number of companies are developing more sophisticated small-particle products that combine small particle technology, multiple functional coatings, and targeted drug delivery. These new developments permit products with sophisticated release profiles and better control of higher potency APIs. 

	1. A. Shanley, “Is Global Regulatory Gridlock Slowing Modernization?” 

Pharm.Tech. Quality Throughout the Supply Chain ebook 

(November 2016) p 27-29, 32.
	2. C. Hroncich, 

Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in the Manufacture of Different Medicinal Products in Shared Facilities

:
	When referring to this article, please cite it as J. Markarian, "Forty Years of Drug Product Manufacturing Advances," 

Articles

Oral solid-dosage and parenteral drug manufacturing equipment and systems have made great strides in safety and efficiency. 

Forty Years of Drug Product Manufacturing Advances

	Along with innovations in manufacturing equipment and facilities, improvements in starting materials, such as antibody selection, have made a difference in the efficiency of biopharmaceutical manufacturing. Catalent’s SMARTag technology, for example, improves antibody-drug conjugate (ADC) manufacturability. 

 spoke with Jennifer Mitcham, director of Business Development, Antibody-Drug Conjugates at Catalent, about this new technology. 

 How does SMARTag improve manufacturability of ADCs?

 Although SMARTag is a chemoenzymatic method, the ‘enzymatic’ portion of the approach refers to a natural, endogenous enzyme that performs a co-translational modification during expression of the SMARTag antibody. We’ve observed that insertion of the enzyme’s recognition sequence does not impact expression levels or target reactivity as compared to the native antibody, and standard purification methods yield antibody material ready to proceed directly into a one-step conjugation. This simplicity is key to robust, efficient scalability of the required manufacturing process for ADCs. We’ve currently scaled multiple SMARTag antibodies up through a number of 500-L runs, observing productivity in excess of 75 pg/cell/day (yielding ~5 g/L) with essentially quantitative conversion to the aldehyde tag. Similarly, the aldehyde-specific chemistry, Hydrazino-Pictet-Spengler (HIPS), which is designed specifically to be well tolerated by proteins and to yield no off-target reactivity, has now been demonstrated to scale very efficiently for the generation of clinical material. Manufacture of SMARTag ADCs also offers an advantage in terms of release analytics since no off-target reactivity has been observed, and lots consistently produce highly homogeneous and stable ADC preparations. We expect the first SMARTag ADC to enter the clinic in early 2018.

	When referring to this article, please cite it as J, Markarian, “Advances in ADCs,” 

New ADC therapies must overcome manufacturing challenges to reach market.

Advances in ADCs

	How did single-use technologies get their start in biopharmaceutical manufacturing? 

 asked Chris Smalley, member of the International Society for Pharmaceutical Engineering’s Disposables Community of Practice and an industry veteran with experience at Wyeth, Sanofi, Johnson & Johnson, and most recently retired from Merck, for a look back at how the single-use revolution began. 

 What were the first applications of single-use technology, and how has the technology changed in the past 40 years? 

 Forty years ago, permanent filter housings with replaceable filter media were the norm. The filter housings were multiuse, inflexible in their use, time-consuming in their preparation, and frequently considered the ‘cold spot’ in the autoclave (i.e., the slowest to reach temperature). With the introduction of single-use filters, flexibility and responsiveness greatly increased, because the filter could be installed in a process stream and the entire system could be autoclaved or gamma-irradiated (providing a higher level of assurance by reducing post-sterilization manipulations) and stored prior to use. Single-use filters were easier to handle because they were lightweight, and they eliminated cleaning steps.

	Forty years ago, the most prevalent container for intravenous (IV) sterile solutions was the colorless glass bottle that needed to be vented to allow the solution to drain, and most times the vent was not even being filtered. When a bottle was dropped by accident, it sounded like a shotgun blast, and of course there was broken glass everywhere. Slowly, single-use bags made from polyvinyl chloride (PVC) were accepted in hospitals across the country. They were robust and didn’t need to be vented with the non-sterile air in the hospital room. The eventual broad use of bags for IV sterile solutions paved the way for expanding the use of other single-use systems in biopharmaceutical manufacturing. More systems were developed that have helped to revolutionize the applications of single-use systems in the past five years. In collaboration with suppliers, the expertise has been developed that enabled single-use systems to expand their use in challenging conditions (e.g., high temperatures, solvents, unique chemistries), which has allowed their evaluation and implementation in different applications. Before, low-risk applications (i.e., media/buffer preparation) adapted single-use systems. Now, the use of single-use systems has expanded to drug substance and drug product applications.

	When referring to this article, please cite it as J, Markarian, “Single-Use Storage Containers and Filters Paved the Way for Single-Use Systems,” 

As commercial manufacturing considers single-use materials, a look shows how industry moved to the technology.

Single-Use Storage Containers and Filters Paved the Way for Single-Use Systems

 Anniversary issue, which will be published in July, the editors interviewed industry experts about the biggest changes the industry has seen in the past 40 years and what they foresee for the future. The trend toward specialized medicines focused on smaller patient populations is leading to smaller production batches and a greater need for flexibility in manufacturing equipment and systems, says Bernd Stauss, senior vice-president of Pharmaceutical Production/Engineering at Vetter Pharma-Fertigung. The increase in highly potent drugs is another driver for equipment advances, notes Christian Treitel, director, Business Development Pharma, Bosch Packaging Technology.

 spoke with Stauss and Treitel about developments in parenteral manufacturing and fill/finish.

 What have been the most significant changes in parenteral pharmaceutical manufacturing and fill/finish in the past 40 years?

 In the past 40 years, we have seen significant increases in automation and the use of barrier systems like restricted access barrier systems (RABS), closed RABS, and isolators. More complex processes can be managed, product quality has improved, and operating costs have been reduced. A wider variety of packaging styles-ready-to-fill syringes and, recently, vials and cartridges-and flexible machine platforms offer pharmaceutical manufacturers the flexibility for different products and requirements. Pharmaceutical manufacturers also more often require 100% in-process checkweighing to prevent product loss of expensive drugs.

 The primary development in parenteral pharmaceutical manufacturing we have experienced over the past 40 years has been the continuous improvement in the quality of the drug manufacturing process. This has had an impact on the entire bio/pharmaceutical industry supply chain. Over this time period, automation grew rapidly and continues to do so today. At Vetter, for example, the use of robots in the production process had already begun by the 1990s.

	From a technological aspect, single-use technology is an emerging trend in the fill-and-finish segment, primarily in the early phases of a drug-development project. A large part of the industry, however, does not believe that single-use equipment will replace stainless-steel technology as a whole. Nevertheless, single-use technology offers a valuable option within special fields of the production process. In our experience, both technologies have their individual pros and cons.

	Today, we see two specific leading cleanroom technologies on the market: RABS technology and isolators. RABS achieves the sterility assurance level (SAL) required by regulatory authorities and allows for rapid product changeover along with high safety. To better meet future industry trends in quality, safety, and flexibility, combining the advantages of both isolator and RABS technology appears to have promising potential for a contract development and manufacturing organization like Vetter. An improved RABS concept, called Vetter CleanRoom Technology (V-CRT), achieves fast and fully-automated decontamination of the cleanroom using hydrogen peroxide.

 One of the primary developments we see is the increase in the overall complexity of individual drug substances which, in turn, affects all parties along the supply chain that are involved in the handling and processing of these substances. Expectations for quality are high, with customers demanding a significant level of oversight.

	Patients are asking for innovative drug-delivery systems that fit better with the ‘mobile lifestyle’ of today. Having access to those systems supports their individual acceptance and compliance. Large areas of the developed world are experiencing growth in aged populations, which has resulted in an increase of associated diseases. As they can often be treated in private settings, there has been an impact on the homecare sector, thus creating a need for appropriate devices, such as pens and autoinjectors. Finally, we have experienced an increase in topics such as digitalization.

 In order to further reduce or avoid human interventions, there will be fully automated production lines with the use of robotics. Connected industry solutions will bring more intelligence into production. These technologies will help achieve higher productivity, safety, and efficiency.

The need for flexibility and higher quality are driving advances in parenteral manufacturing and fill/finish equipment. 

Looking at Trends in Parenteral Manufacturing

	Twin-screw extruders, long used by the plastics industry for continuous mixing of polymer compounds, are now also well established as continuous mixing equipment for polymeric excipients and APIs. GMP materials of construction, easily cleanable designs, and equipment for contained feeding of high potency ingredients are all commercially available. Pharmaceutical applications for twin-screw extrusion, as well as practical information for setup, cleaning, and validation, were discussed at the Leistritz Pharmaceutical Extrusion Seminar (June 7–8, 2017, Clinton, NJ).

	An important use of pharmaceutical hot-melt extrusion (HME) is the bioavailability enhancement of poorly-water soluble APIs. In HME, twin-screw extruders are used to dissolve and mix the poorly water-soluble, hydrophobic APIs (typically below their melting temperature) in water-soluble, hydrophilic excipients (typically 50–100 ËC above their glass transition temperature) to create “amorphous solid solutions” that have increased bioavailability relative to their crystalline counterparts. One challenge is that the amorphous forms should remain stable (i.e., not revert to crystalline form) at ambient temperature, typically for a two-year shelf-life, noted Nicolas Ioannidis, research engineer at the Polymer Processing Institute, in a presentation at the seminar.

	Twin-screw extrusion can also be used to continuously mix APIs with excipients so that the mixture can be formed into a drug delivery device, such as a contraceptive ring or an implantable rod for long-acting, controlled release and local drug delivery. Merck, for example, is investigating an implantable rod to deliver an antiretroviral HIV treatment. In oral form, repeat administration or large tablets would be required, but an implant could improve patient compliance, explained Seth Forster, scientist at Merck Research Laboratories, in a presentation at the seminar. The API-excipient mixtures for such products could be either amorphous solid dispersions or, if API solubility is not a concern, dispersions of a crystalline API in the polymer. “Extrusion is an elegant way to make a complex structure,” concluded Forster.     

	Foster Delivery Science opened a new cGMP manufacturing facility in 2015 that is dedicated to using twin-screw extrusion to make polymer blends for various drug delivery dosage forms, including drug-delivery implants, and is seeing growing use in these areas, noted Tony Listro, vice-president of Foster Delivery Science. At the seminar, he described a direct extrusion process for a drug-eluting dental implant for local drug delivery, in which the API and excipient are mixed and then formed into a monofilament, all within one process. In another example, he described how drug products mixed on a twin-screw extruder can be formed into a film for transdermal delivery.

	“The evolution of twin-screw extrusion for continuous mixing applications is analog to what happened 50 years ago in the plastics and food industries,” explained Charlie Martin, president and general manager at Leistritz, which hosted the seminar. “This technology has been well proven for decades in a 24-hour-per-day industrial setting making many of the most sophisticated products we use every day. The next stage of development for pharmaceutical applications will be downsizing and applying existing extrusion technologies for multifunctional and specialty dosage forms.”

At an industry seminar hosted by Leistritz Extrusion, experts explained the use of extrusion equipment to mix polymeric excipients with APIs for solubility enhancement and for multifunctional and specialty dosage forms, including implants. 


Twin-Screw Extruders Serve the Pharma Industry

	Continuous manufacturing of pharmaceuticals could reduce the inefficiencies found in batch manufacturing. It creates an opportunity to implement more modernized manufacturing processes, which lead to better quality end products. This technology could also help prevent drug shortages through faster and more responsive supply chains. Continuous technologies offer the potential to replace the outdated "quality by testing" regime currently employed by the industry with a more robust "quality by design" system, which is possible because of the improved process understanding and  robust control strategies gained through continuous processing, said Bayan Takizawa, co-founder and chief business officer at CONTINUUS Pharmaceuticals, at a conference session on continuous manufacturing at INTERPHEX on March 21, 2017. Industry, academia, and regulators have spent significant time and money over the past decade to develop pharmaceutical continuous manufacturing for solid-dosage drugs, and commercial approvals-such as Janssen and Vertex for drug products and Lilly, GSK, and Lonza for APIs-have been the fruit of this labor.

	Although these processes have adopted continuous unit operations, overcoming the disconnect between drug substance and drug product and moving to an end-to-end continuous system could produce even greater rewards, suggested Takizawa. Both CONTINUUS and Novartis are both working on end-to-end systems launched from work at the Massachusetts Institute of Technology (MIT). Novel process technologies and an integrated, system-wide approach may eliminate the “corrective steps” (i.e., granulation, compression, blending, milling) necessitated by existing processes, he explained; development continues in this area.     


	An ongoing challenge for continuous processing is integrating unit operation equipment and control systems. More integrated systems are becoming available, however, noted Doug Hausner, associate director at the Engineering Research Center for Structured Organic Particulate Systems (C-SOPS), at the INTERPHEX session.

	One example is a consortium including GEA, G-CON, and Pfizer that developed the Portable, Continuous, Miniature, and Modular (PCMM) solid-dosage system; GSK joined the consortium in 2015. Pfizer’s prototype PCMM won the International Society for Pharmaceutical Engineering (ISPE) Facility of the Year Awards (FOYA) for the 2016 Equipment Innovation category, and GEA’s ConsiGma continuous system won an Excellence in Pharma award at CPhI 2016. 

	At L.B. Bohle’s Technology Center in Ennigerloh, Germany, customers can test products on a continuous processing system that includes blending, dosing, tableting, and coating; process analytical technology; and an integrated control system.  The modular system allows wet granulation, roller compaction, or direct compression, explained company representatives at the INTERPHEX exhibit.

	Glatt’s continuous solid-dosage processing systems are operating at its Innovation Center in Binzen, Germany, which was inaugurated in November 2016. The system can use direct compression, mid-shear wet granulation (in a blender), or high-shear wet granulation (in a twin-screw extruder); the company is also working to integrate its fluid-bed spray granulation into the continuous system, explained Ed Godek, manager of process technology in the Glatt Equipment and Engineering Division, at INTERPHEX. Glatt has been developing the wet granulation continuous system with Thermo Fisher Scientific’s Pharma 11 twin-screw extruder for the granulation step and Innopharma’s Eyecon process analytical technology (PAT) tools. Eyecon measures particle size at the outlet of the wet-granulation process as part of a feedback control loop that keeps particle size within specification and also after the dryer. Process control for the system was done in-house by Glatt.

	Integrating process control is an important, but complex, piece of continuous processing technology. Process control system experts should be involved as early in the development process as possible, suggested Pamela Bruen Docherty, Life Sciences Industry manager USA, at Siemens, in a presentation at INTERPHEX. Model-predictive control handles multiple inputs and outputs and is needed for the advanced process control that connects the pieces of a continuous system, she explained. Many advances in system control and process modeling, in both solid-dosage and biopharmaceuticals, have been achieved in the past several years.


	Many companies have developed the required technical capabilities and are poised to implement them, but seem to be in a “wait and see” mode, commented Hausner at the INTERPHEX conference session. Most of the technical barriers have been overcome by the industry as a whole, he noted, but having the right people, knowledge, and equipment at an individual company can be a challenge. A “big picture” mindset, rather than evaluating the advantage of the new technology on a product-by-product basis, is needed to promote high-level support for capital expenditures, said Hausner. The perception of regulatory uncertainty, particularly in large, important markets, such as Europe, is another limiting factor.  


	FDA has been quite clear on its support of continuous manufacturing over the past several years. FDA’s message has been consistent that it sees no regulatory hurdles for implementing continuous manufacturing, it supports the implementation of continuous manufacturing using a science- and risk-based approach, and it sees continuous manufacturing as consistent with FDA’s quality initiatives (1,2).

	Other regulatory bodies have perhaps not been as vocal in their support of continuous manufacturing as FDA has been, but the European Medicines Agency (EMA) has begun to express support and recently clarified its position, providing further technical specificity. At the 3

 FDA/PQRI Conference on Advancing Product Quality (March 22­–24, 2017), EMA’s Dolores Hernan noted that the current regulatory framework allows continuous manufacturing, and although specific guidelines are not available, the existing ones are supportive of this approach (3).

	Both FDA and EMA recommend communicating with the agencies early in development (2,3). “The toolbox is out there, and EMA and FDA want you to come talk with them to show them you understand these new tools as you go to use them,” notes Hausner.


	Several conferences in 2016, such as the International Society for Pharmaceutical Engineering (ISPE)’s 

, the FDA-American Institute of Chemical Engineers (AIChE) 

Workshop on Adopting Continuous Manufacturing

 International Symposium on Continuous Manufacturing of Pharmaceuticals

 organized by the Massachusetts Institute of Technology (MIT) and the Continuous Manufacturing and Crystallization Consortium (CMAC), have worked to increase understanding and to promote adoption of continuous manufacturing.

	In May 2017, the global International Institute for Advanced Pharmaceutical Manufacturing (I2APM) is hosting the 

Emerging Pharmaceutical Manufacturing Summit

, May 8–9, 2017 in Malta, to bring together first- and second-wave technology adopters, regulators, and academics. C-SOPS, one of the founding groups of I2APM and one of the event organizers, hopes that European regulators, in particular, will benefit from seeing the examples of commercially approved implementations of continuous manufacturing.

	The United States Pharmacopeial Convention (USP), in collaboration with C-SOPS, hosted a workshop in the US in 2016 on continuous manufacturing, one of the outcomes of which was a new expert panel that is now working to standardize terms and characterize materials specific to what it is calling PCM [pharmaceutical continuous manufacturing]. USP and C-SOPS signed a memorandum of understanding in February 2017 as part of their commitment to collaborate and work to make PCM more widely available (4). USP is hosting a 

on May 16–17, 2017 to introduce PCM to Indian pharma companies, particularly generic drug companies.

FDA Perspective on Continuous Manufacturing

,” Presentation at IFPAC Annual Meeting (Baltimore, Jan. 2012).	

Continuous manufacturing: Challenges and opportunities. EMA perspective

 FDA 3rd FDA/PQRI Conference on Advancing Product Quality 22-24 March 2017. 	

		USP, “Exploring Continuous Manufacturing Technology and Applications in the Pharmaceutical Industry,” (March 13, 2017), 

http://qualitymatters.usp.org/exploring-continuous-manufacturing-technology-and-applications-pharmaceutical-industry

” Presentation at MIT-CMAC ISCMP (Cambridge, MA, May 20, 2014). 

Although technical paths for continuous solid-dosage manufacturing have been laid out and equipment and control systems have been developed, industry is slow to move forward.